tbuckley/cabot-search huggingface dataset:
Abstract 3096: Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics
Authors: Angelie Matar, Yuliya Marusyk, Sujeewa Ranatunga, Tegan Rowsell, Narmin Amin, Hannah Walker, Timothy Tran, Kathy Yang, Derek Duckett, Gary Reuther, Harshani Lawrence, Nicholas Lawrence
Journal: Cancer Research (2023)

Abstract Activated CDC42-associated tyrosine kinase 1 (ACK1) is an enzyme encoded by the TNK2 gene. Studies have shown ACK1 phosphorylates proteins in oncogenic pathways active in lung, leukemia, ovarian, breast, and prostate cancers. Some of these phosphorylated proteins include tyrosine-kinase B (AKT), androgen receptor (AR), tumor suppressor WWdomain oxidoreductase (WWOX), proto-oncogene tyrosine-protein kinase (FYN), and growth factor receptor bound protein 2 (Grb2). ACK1 plays a pivotal role in leukemia, breast, and prostate cancer making it an attractive anticancer drug target. The development of novel ACK1 inhibitors using a pyrrolopyrimidine scaffold is described using molecular modeling and structure-activity relationships (SAR) studies. The synthesis of a focused library using a fragment-based design strategy will be highlighted as well as progress to optimize these compounds for potency, selectivity, and cell permeability. To gain structural insights for the development of novel, potent and selective ACK1 inhibitors, we have obtained X-ray structures of our compounds bound to human ACK1. We will describe the use of molecular docking to predict the binding mode of our compounds using both reported and our new ACK1 co-crystal structures. The key residues in the ATP binding pocket of ACK1 that are exploited for inhibitor design and kinase selectivity and synthetic routes to promising compounds will be discussed. We will present the KDs of the most potent compounds derived using a differential scanning fluorimetry (DSF) thermal shift assay and cellular activities in UKE1 leukemia and MB-231 breast cancer cell lines. We will present preliminary assessment of drug-like properties, used to optimize the inhibitor class for selection of a candidate for mouse studies. Overall, our work will highlight identification/optimization of novel ACK1 inhibitors via a fragment-based approach using pyrrolopyrimidine scaffolds and their potential use as anticancer agents. We will present the synthesis, SAR analysis, and the binding mode of these inhibitors. Citation Format: Angelie Matar, Yuliya Marusyk, Sujeewa Ranatunga, Tegan Rowsell, Narmin Amin, Hannah Walker, Timothy Tran, Kathy Yang, Derek Duckett, Gary Reuther, Harshani Lawrence, Nicholas Lawrence. Development of pyrrolopyrimidine-based ACK1 inhibitors for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3096.
Abstract 4832: Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC
Authors: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC) is a highly aggressive disease with a dismal prognosis associated with high rates of treatment resistance and disease recurrence. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for locally advanced non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1) has been introduced as first-line NSCLC treatment, yet long-term disease control occurs in less than 25% of patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the need for novel synergistic therapies to sensitize refractory NSCLC tumors to anti-cancer treatment. Tumor hypoxia has been associated with treatment resistance for decades, yet its role in the clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS) and the expression of validated hypoxia-regulated genes (Buffa hypoxia score). The oxygen-consumption expression signature was implemented in software that enables the calculation of numerous tumor microenvironment expression signatures, called tmesig. Furthermore, we have observed a direct positive correlation between the hypoxia expression signatures levels in NSCLC patient samples and the copy number amplification (CNA) of essential OXPHOS genes. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may indirectly regulate oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function, which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC. Citation Format: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko. Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4832.
Abstract 2656: Reversible chemical modification of antibodies: A complementary approach to tuning FcγR binding that maintains anti-tumor activity while mitigating peripheral immune activation
Authors: Philip N. Moquist, Chris I. Leiske, Noah A. Bindman, Xinqun Zhang, Nicole Duncan, Weiping Zeng, Serena W. Wo, Abbie Wong, Clark M. Henderson, Karalyne Crowder, Haley D. Neff-LaFord, Django Sussman, Shyra J. Gardai, Matthew R. Levengood
Journal: Cancer Research (2023)

Abstract Modification of effector function has proven to be an effective modality for optimizing activity and tolerability of therapeutic antibodies. Currently available methods to modulate effector function include the introduction of point mutations in the Fc region and glycan engineering of the antibody. Here we present an alternative and complementary method of tuning effector function utilizing a conjugation-based approach. This methodology uses conjugation of polyethylene glycol (PEG) to native cysteines of an antibody to impair FcγR binding of antibodies to innate immune effector cells. Utilizing maleimide or disulfide conjugation techniques, attenuated effector function can be either permanent or restored over time through a de-conjugation process. Impacts of PEGylation on FcγR binding, signaling, and restoration of function were assessed in vitro and in vivo. As a proof-of-concept, the lead technology was applied to an agonist CD40 antibody, which resulted in significant reductions in systemic cytokine production in hCD40 mice and non-human primates, while demonstrating retained efficacy and improved pharmacokinetics. Additionally, we combined the conjugation technology with glycan engineering and FcγR enhancing point mutations to impart unique effector function profiles to clinical antibodies. This simple, modular approach can be rapidly applied to existing antibodies to reduce immune-driven toxicities, such as infusion reactions, and optimize effector function activity. Citation Format: Philip N. Moquist, Chris I. Leiske, Noah A. Bindman, Xinqun Zhang, Nicole Duncan, Weiping Zeng, Serena W. Wo, Abbie Wong, Clark M. Henderson, Karalyne Crowder, Haley D. Neff-LaFord, Django Sussman, Shyra J. Gardai, Matthew R. Levengood. Reversible chemical modification of antibodies: A complementary approach to tuning FcγR binding that maintains anti-tumor activity while mitigating peripheral immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2656.
Abstract 2294: The development of 3D deformable microfilter with a DNA aptamer for detecting circulating tumor cell
Authors: Masaaki Iwatsuki, Yuta Nakashima, Yusuke Kitamura, Keiichiro Yasuda, Hideo Baba
Journal: Cancer Research (2023)

Abstract Introduction: The analysis of blood for circulating tumor cells (CTCs) has opened new avenues for cancer diagnostics, including early detection, risk assessment and staging. However, research about CTCs has been challenging due to the rarity of CTCs in bloodstream. We develop a three-dimensional deformable microfilter with a EpCAM aptamer for detecting CTCs and conduct a pilot study to evaluate the efficacy of our novel detection devise. Methods: The cancer cell suspension with blood from healthy volunteers and human blood sample from cancer patients are passed through the microfilter and counted by fluorescence microscope. We also countered the number of cancer cells by CellSearch eq \o\ac(○,R)R. The peripheral blood sample from upper gastrointestinal cancer patients are also passed through the microfilter. Results: Even in the presence of 100 times normal cell, cancer cells were captured on the substrate successfully from cell suspensions with several mixing ratios. We can capture cancer cells suspended with PB from healthy volunteer more effectively compared with CellSerach®. A total of 15 patients and 40 samples were enrolled (Stage I: II: III: IV: recurrence=1:1:3:4:6). The average number of CTCs was 3.1 cells/ml (0-6.3 cells). Among the 15 patients with GC, CTCs were detected by our system in 13 patients. Even in GC patients suspected with peritoneal dissemination without definitive mass by imaging, CTCs were successfully detected. For the patients who were measured multiple times with clinical time course, we found a close correlation between CTC number and CEA level or image assessment. Conclusion: We successfully detected CTCs in the patients with upper gastrointestinal cancer patients. Although our pilot study indicates the potential of a novel devise to capture CTC effectively, a large scale of validation is needed to confirm the clinical utility. Citation Format: Masaaki Iwatsuki, Yuta Nakashima, Yusuke Kitamura, Keiichiro Yasuda, Hideo Baba. The development of 3D deformable microfilter with a DNA aptamer for detecting circulating tumor cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2294.
Abstract 2312: Single-cell low pass whole genome sequencing for copy-number profiling in circulating tumor cells from prostate, non-small cell lung and breast cancers
Authors: Danyi Wang, Giuseppe Locatelli, Ioannis Gounaris, Juergen Scheuenpflug, Zheng Feng
Journal: Cancer Research (2023)

Abstract Background: Circulating tumor cells (CTCs) have been considered as an alternative to tissue biopsy for providing both germline-specific and tumor-derived genetic variants. Copy number variations (CNVs) play an important role in molding the genomes of cancers and have been shown the clinical value for prognostic signature and therapeutic target. The current study aimed to evaluate CNVs at single-cell resolution and explore the potential clinical utility of tracking this key mechanism of cancer progression. Methods: Blood samples were collected in Streck tubes from 40 stage II-IV cancer patients (5 prostate cancer, 15 non-small lung cancer (NSCLC), 20 breast cancer (BC)) before treatment. CTCs was identified as cells containing an intact nucleus, without CD45 expression, and with cytokeratin expression. Genomic analysis of chromosomal CNVs by low pass whole genome sequencing (Lp-WGS) and number of large-scale transitions (LSTs) calculation was performed in the CTCs. Results: A total of 9 CTCs from 4 prostate cancer, 70 CTCs from 7 NSCLC, 22 CTCs from 9 breast cancer patients, representing a range of sizes, shapes, and protein expression levels of cytokeratin were identified. A total of 84 individual CTCs were successfully sequenced from 20 patients (1-6 CTCs/patient). The selected highlights for gene CNVs include: 1) CXCR4 and ATM were detected as loss on single cell CTC (scCTC) level in BC; 2) MED12, an important regulator for maintaining accurate cytokinesis and survival, was detected as loss on scCTC level in NSCLC. A wide range of LST scores were observed among the 20 patient samples. Cell morphology analysis, phenotypic heterogeneity biomarker analysis and homologous recombination deficiency (HRD) biomarker analysis using a previously developed HRD classifier1 trained on genomic markers is still ongoing. Conclusion: Our data demonstrated that Lp-WGS of DNA from CTCs can detect CNVs loss and assess disease heterogeneity at the single-cell level. Since genome-wide CNV profiles can be used to characterize genomic instability, it is anticipated that the integrative analysis of morphology and genomics in CTCs can potentially complement tissue and/or ctDNA analysis to determine HRD, enabling in-depth investigation of tumor heterogeneity and individualized clinical assessment. Citation Format: Danyi Wang, Giuseppe Locatelli, Ioannis Gounaris, Juergen Scheuenpflug, Zheng Feng. Single-cell low pass whole genome sequencing for copy-number profiling in circulating tumor cells from prostate, non-small cell lung and breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2312.
Abstract 2110: Reprogramming of DNA methylation in NAFLD progression
Authors: Hanyong Go, Seon-Kyu Kim, Mirang Kim
Journal: Cancer Research (2023)

Abstract NAFLD has several stages in its progression that can lead to non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma (HCC). Whereas NAFL is a simple steatosis, NASH is characterized by cell injury, inflammation, and hepatocyte ballooning that may further progress to fibrosis, cirrhosis, and HCC. DNA methylation is a relatively stable epigenetic mechanism that can regulate gene expression patterns to establish cell identity. Here we investigated liver DNA methylation in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. NAFLD is associated with abnormal DNA methylation, Advanced NAFLD is associated with hypomethylation of genes involved in TNF receptor signaling and apoptosis, and hypermethylation of genes associated with lipid metabolism, digestion and transport. We suggest that reprogramming of DNA methylation contributes to NAFLD progression and aberrant DNA methylation could be a predictive biomarker of NASH associated HCC. Citation Format: Hanyong Go, Seon-Kyu Kim, Mirang Kim. Reprogramming of DNA methylation in NAFLD progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2110.
Abstract 1: Mouse models of cancer available from The Jackson Laboratory
Authors: Jason Beckwith, Jen Merriam, Alicia Valenzuela, Darcy Pomerleau, Crystal Davis
Journal: Cancer Research (2023)

Abstract Genetically defined mice are a cornerstone of cancer research. The Jackson Laboratory (JAX) offers more than 13,500 unique mouse lines to the scientific community, many useful in advancing cancer research. Available are mouse models for specific cancers, xenograft recipients, immunodeficient platforms for PDX studies and multi-purpose tool strains having CRISPR/Cas9 expression, conditional/inducible expression (Cre-lox, FLP-frt, Tet-On/-Off), optogenetic function and calcium-sensing technologies. This poster will highlight some recently added models, more than 150 of which have cancer research applications. The portfolio of strains useful for transplantation/engraftment and “humanized” mouse research continues to expand and complement the NSG (NOD scid IL2rγc-/-) model as ideal tools for engraftment with a wide range of malignant or non-malignant human or mouse tissues. Fluorescent protein-expressing strains include the Traffic Light Reporter models for tracking of DNA repair pathways and the Gene Editing Reporter models for detection of homology directed repair (HDR) or non-homologous end joining (NHEJ) repair events. As a tool for gene targeting, the RosaBxb-GT/GA mice are designed to allow insertion of ~40kb of desired DNA sequence into the Gt(ROSA)26Sor locus. In addition to safeguarding each strain by cryopreservation, JAX has a comprehensive genetic quality control program that confirms mutation identity and genetic background, and screens for unwanted alleles (such as stray GFP, Cre, neo, etc.). Search the comprehensive collection of innovative mouse models using our improved JAX Mouse Search site (mice.jax.org). This resource includes models created by many generous donating institutions. Researchers are encouraged to donate their mouse lines via a very short Strain Submission form (jax.org/donate-a-mouse). Please also visit the JAX Oncology webpage for cancer research related strains and resources (jax.org/jax-mice-and-services/solutions-by-therapeutic-area/oncology). JAX is supported by the NIH, The Howard Hughes Medical Institute and other private charitable foundations. Citation Format: Jason Beckwith, Jen Merriam, Alicia Valenzuela, Darcy Pomerleau, Crystal Davis. Mouse models of cancer available from The Jackson Laboratory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1.
Abstract 3813: Role of CDKN2B antisense RNA 1 in Epstein-Barr virus associated gastric carcinoma
Authors: Keila Torres, Wilda Olivares, Gonzalo Carrasco, Andres Rodriguez, Alejandro H. Corvalan
Journal: Cancer Research (2023)

Abstract Background: Epstein-Barr Virus (EBV)-associated gastric carcinoma (GC) (EBVaGC) is a subtype of GC which represents approximately 10% of this tumor. CDKN2B antisense RNA 1 (CDKN2B-AS1) is a long non-coding RNA associated with chronic diseases like cardiovascular disease and cancer. This study aimed to evaluate if the loss of CDKN2B-AS1 shifted the balance of the competing endogenous RNA (ceRNA) networks favoring an apoptosis resistant phenotype through ebv-miR-BART4-5p/BID in EBVaGC. Material and Methods: Seven gastric cancer cell lines were used to determine the expression of CDKN2B-AS1. Specific cell lines were used for CDKN2B-AS1 inhibition assays, the transfection of ebv-miR-BART4-5p and the binding between CDKN2B-AS1 and ebv-miR-BART4-5p. The detection of BID protein was determined by Western Blot. To validate the in vitro results, we detected CDKN2B-AS1, BID, and ebv-miR-BART4-5p expression levels by RT-qPCR in four EBVaGC positive and five negative cases. Apoptosis was detected by in situ hybridization (ISH). Results and Discussion: CDKN2B-AS1 is expressed at higher levels in NCI-N87 and SNU-1 cell lines and at lower levels in AGS and KATO-III. A significant decrease in BID protein expression was observed after co-transfection with ebv-miR-BART4-5p and CDKN2B-AS1 inhibitor. However, these results were not significant at mRNA level. The luciferase assay validated the predicted binding between ebv-miR-BART4-5p and CDKN2B-AS1. In EBVaGC samples, a significant decrease in BID expression and cleaved caspase-3 in the presence of miR-BART4-5p was observed. Our results show that decreasing CDKN2B-AS1 expression favors viral miR binding on BID mRNAs through ceRNA networks. Also, these results could explain why positive EBVaGCs have lower apoptosis rate than EBVaGC negative cases. Grant support: ANID/FONDECYT/POSTDOCTORADO/3201028, CONICYT-FONDAP-15130011, FONDECYT-1191928 Citation Format: Keila Torres, Wilda Olivares, Gonzalo Carrasco, Andres Rodriguez, Alejandro H. Corvalan. Role of CDKN2B antisense RNA 1 in Epstein-Barr virus associated gastric carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3813.
Abstract 1842: The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates
Authors: Wei Li, Yixuan Xu, Xin Zhou, Dan Zhu, Meng Xiao, Yulin Zhou, Zhijie Yang, Haodong Li, Bo Pang, Xinghai Song, Yan Xiao, Wenting Shi, Qian Qian, Qingyang Gu
Journal: Cancer Research (2023)

Abstract Cytokines are indispensable regulators of innate and adaptive immunity that transfer signals between cells over short distances. Given their abilities to initiate and activate immune responses, cytokines have long been utilized in cancer therapy, whereas there are limitations, short half-life, pleiotropism, functional redundancy, and side effects, slow down the wide application of cytokine therapy. Thus, evaluating the pharmaceutical properties of cytokines or their translated forms, such as supercytokines, immunocytokines, engager cytokines, and synthetic cytokines, in non-human primates shall be a substantial approach to guide and define clinical trial strategies of cytokine-based therapies. In this study, Interleukin-15 (IL-15) is preferably focused due to its potential in proliferating natural killer cells and cytotoxic T lymphocytes by which host’s immunity was boosted to fight against tumor progression. To evaluate the safety and pharmacodynamics of IL-15 in vivo, rhesus macaques were administered intravenously with recombinant human IL-15 (rhIL-15). We revealed that intravenous administration of rhIL-15 to rhesus macaques caused a slightly weight loss and neutropenia, while no other abnormalities were observed during the whole study. Moreover, the level of C-reactive protein (CRP) was found significantly elevated which was consistent with the increased abundance of MCP1, CCL4, and IL-RA chemokines in serum, suggesting that IL-15 treatment induces acute inflammatory response. Furthermore, flow cytometry analysis showed the activation, proliferation and expansion of memory T and NK cells after receiving IL-15. In conclusion, our study deepens the understanding of T and NK cell homeostasis after IL-15 administration in NHPs and may offer critical clinical strategies for human trials. Citation Format: Wei Li, Yixuan Xu, Xin Zhou, Dan Zhu, Meng Xiao, Yulin Zhou, Zhijie Yang, Haodong Li, Bo Pang, Xinghai Song, Yan Xiao, Wenting Shi, Qian Qian, Qingyang Gu. The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1842.